Influenza A viruses pose a serious threat to human health, causing seasonal epidemics and occasional pandemics that result in significant morbidity and mortality worldwide. The most effective method of protection against seasonal influenza virus is vaccination; however, vaccines are ineffective against novel influenza viruses, as there is little or no cross protection afforded by seasonal vaccines. Because production of sufficient quantities of influenza vaccine requires at least 6 months, and establishment of herd immunity is a lengthy and complicated process, people of all ages are highly vulnerable to novel influenza virus strains. To overcome the limitations of the available influenza vaccines, small molecule inhibitors are still a vital need as an alternative treatment to influenza virus infection Unfortunately, resistance has rendered existing therapeutics much less effective, and the need remains for new antiviral drugs to combat future epidemics and pandemics. We have recently identified Adenosine Deaminase Acting on double stranded RNA (ADAR1) as a host factor critical to the replication of multiple strains of influenza viruses. Importantly, we have determind that the non- structural protein 1 (NS1) of influenza virus interacts with ADAR1 and enhances its RNA editing activity, which is necessary for efficient viral replication and maintenance of progeny fitness. Our data demonstrates that influenza virus replication is reduced 10-1000 fold in cells lacking ADAR1 or cells expressing a catalytically inactive ADAR1; furthermore, viruses passaged in the absence of ADAR1 fail to acquire resistance mutations. We have developed a luciferase-based assay to measure the deaminase activity of ADAR1 and have validated its robustness in the high throughput screening (HTS) system. We will screen for small molecule inhibitors that disrupt ADAR1-NS1 interactions and/or directly inhibit ADAR1 deaminase activity, improve the potency and selectivity of identified compounds by SAR studies, perform preclinical evaluation studies in mice with influenza viruses, and develop advanced lead compounds suitable for further preclinical testing.